The present invention relates generally to the field of degradable polymers. More particularly, the present invention provides a method for determining oligomeric degradation products of biodegradable polymers either alone or simultaneously with surface concentration of drug in polymer-drug blend matrices and the drug release characteristics of such blends. This information is useful in determining degradation reaction kinetics of biodegradable polymers and biodegradable polymer-drug blend matrices and the drug release characteristics of such blends. Synthetic biodegradable polymers have been used in clinical applications for decades. Some relevant applications include surgical implants, wound healing materials, absorbable sutures and drug delivery devices. Among issues important in developing biomedical applications based on polymer biodegradability are the properties of degradation (such as rate, mechanism, by products, etc.) of the polymer material. The study of hydrolytic degradation of biodegradable polymers has been a research focus in the past few decades with in vivo investigations of biopolymer implants being the major clinical investigation method. Direct monitoring of the weight loss of polymer implants and histological observations provides macroscopic information on the hydrolytic degradation. A drawback of this method is that it is very time consuming.
For the in vitro investigation of hydrolytic degradation of biodegradable polymers, many bulk characterizations have been developed. Properties such as tensile strength, thermal properties, mass loss, and decrease in molecular weight have been measured. Techniques used include: differential scanning calorimetry (DSC), gravimetry, gel permeation chromatography (GPC), size exclusion chromatography (SEC), FTIR, NMR, X-ray diffraction and laser diffractometry.
Among the surface sensitive microscopic and spectroscopic techniques, methods such as scanning electron spectroscopy (SEM) and atomic/scanning force microscopy have become important means for studying biodegradation of polymers. The surface microscopic techniques, however, do not provide chemical compositional or structural information.
A class of biodegradable polymer that has attracted considerable attention for the design of novel drug delivery systems is the polyesters. These include poly-(xcex1-hydroxy acids), poly(xcex2-hydroxy acids), poly(xcex1-malic acids), pseudopoly(xcex1-amino acids), their copolymers, and mixtures thereof. Of particular interest are the polyesters with pendant carboxylic acid groups. These carboxylic acid groups may be functionalized to manipulate material properties and are thought to have a catalytic effect on the hydrolytic scission of the ester bonds, increasing the degradation rate.
The drug release kinetics from drug/biodegradable polymer blend matrices is complicated due to both polymer erosion and drug diffusion through preformed microporous channels within the matrices. Factors such as morphology and crystallinity of a polymer, formulation, drug molecular size and solubility may have significant influence not only on the degradation of drug delivery devices, but also on the release profile of a drug. Furthermore, it has been reported that it is difficult to predictably control drug release over a desired period. This is suspected as being due more to an initial burst (rapid release) of drug combined with the process of relatively faster drug diffusion than polymer degradation of the matrices. Although a number of studies have been directed toward drug release profiles and correlating these results with polymer degradation kinetics, little attempt has been made to simultaneously determine both, especially with respect to the surface/interface chemistry for the induction phase of bulk erosion of drug/biodegradable polymer blend matrices.
Thus, conventional techniques do not provide information to quantitatively describe the initial burst of drug release with the polymer degradation kinetics at the induction phase of bulk erosion of the blend matrices. Thus, there is a pressing need to develop powerful and fast methods for evaluating and screening the degradation kinetics of biodegradable polymers and drug release profile in the induction period of bulk erosion of biodegradable polymer blend matrices.
The present invention provides a novel method for simultaneously determining both surface concentration of a drug and degradation kinetics of a biodegradable polymer/drug blend matrix by using Time-of-Flight Secondary Ion Mass Spectrometry (ToF SIMS) measurements. The method comprises simultaneously determining surface concentration of a drug in the polymer/drug matrix and reaction kinetics of a degradable polymer in the polymer/drug matrix by the following steps: providing a polymer/drug matrix, initiating degradation of the polymer/drug matrix, subjecting the degraded polymer/drug matrix to high mass and low mass ToF SIMS spectral analysis, identifying and quantifying oligomers from the high mass ToF SIMS over a period of time, identifying and quantifying surface drug from the ToF SIMS spectra over the same period of time, and calculating the rate of formation of one or more oligomers and the rate of change of surface concentration of drug.
In yet a further embodiment of the present invention, oligomers of a hydrolyzed biodegradable polymer are identified and quantified by the following steps: providing a biodegradable polymer, initiating hydrolytic degradation of the biodegradable polymer, subjecting the degraded biodegradable polymer to high mass ToF SIMS spectral analysis and identifying and quantifying oligomers from the high mass ToF SIMS spectral analysis.